Pharmaceutical compositions and methods of inhibiting histamine activity with thiourea derivatives

ABSTRACT

Pharmaceutical compositions and methods of inhibiting histamine activity with N-heterocyclic-alkylthioureas.

United States Patent Durant et al.

PHARMACEUTICAL COMPOSITIONS AND METHODS OF INHIBITING HISTAMINE ACTIVITY WITI-I TI-IIOUREA DERIVATIVES Smith Kline & French Laboratories Limited, Welwyn Garden City, England Filed: Dec. 26, 1973 Appl. No.: 427,774

Related US. Application Data Division of Ser. No. 312,438, Dec. 6, 1972, Pat. No. 3,808,336, which is a continuation-in-part of Ser. No. 145,024, May 19, 1971, abandoned.

Assignee:

Foreign Application Priority Data June 25, 1970 United Kingdom 30834/70 Oct. 15, 1970 United Kingdom 49007/70 Jan. 22, 1971 United Kingdom 2918/71 US. Cl. 424/263; 424/269; 424/270; 424/273 [451 Sept. 23, 1975 [51] Int. CI. ..A61K 31/41; A6IK 31/44; A61K 31/415; A61K 31/425 [58] Field of Search 424/269, 263, 270

[56] References Cited UNITED STATES PATENTS 3,558,640 1/1971 Shen et al. 260/309 FOREIGNPATENTS OR APPLICATIONS 1,069,117 5/1967 United Kingdom 424/309 QTHER PUBLICATIONS Novikov et'aj., Chemical Abstracts, 70, 77726U, 4/28/69.

Foggio; William H. Edgerton [5 7] ABSTRACT Pharmaceutical compositions and methods of inhibiting histamine activity with N-heterocyclicalkylthioureas.

10 Claims, No Drawings This is a division of application Ser. No. 312,438 filed Dec. 6, 1972 now US. Pat. No. 3,808,336 which is a continuation-in-part of Ser. No. 145,024, filed May 19, 1971 now abandoned.

This invention relates to pharmaceutical compositions and methods of inhibiting histamine activity, and more particularly to inhibiting H-2 histamine receptors, with thiourea derivatives. The thiourea derivatives can exist as the addition salts, but for convenience, reference will be made throughout this specification to the parent compounds.

It has for long been postulated that many of the physiologically active substances within the animal body, in the course of their activity, combine with certain specific sites known as receptors. Histamine is a compound which is believed to act in such a way but, since the actions of histamine fall into more than one type, it is believed that there is more than one type of histamine receptor. The type of action of histamine which is blocked by drugs commonly called antihistamines (of which mepyramine is a typical example) is believed to involve a receptor which has been designated by Ash and Schild (Brit. J. Pharmac. Ch'enzot/zer. 27:427, 1966) as l-l-l. The thiourea derivatives of the pharmaceutical compositions and methods of the present invention are distinguished by the fact that they act at histamine receptors other than the l-l'-l receptor, that is they act at l-l-2 histamine receptors which are described by Black et al., Nature 236, 385 (1972).

Black et al., cited above, page 390, column 2, state the following: Mepyramine has been defined as an II.- receptor antagonist and burimamide has now been defined as an l-l -receptor antagonist. Used alone, burimamide can antagonize those responses to histamine, such as stimulation of acid gastric secretion, which cannot be blocked by mepyramine; histamine apparently activates l-l -receptors to produce these effects. Thus, from the Black et al. paper, l-l-2 histamine receptors are those histamine receptors which are not inhibited by mepyramine but are inhibited by burimamide. Thus they are of utility in inhibiting certain actions of histamine which are not inhibited by the above-mentioned antihistamines. Inhibitors of l-l-2 histamine receptors are useful, for example, as inhibitors of gastric acid secretion and as anti-inflammatory agents particularly where the inflammation is kininmediated.

The thiourea derivatives which are the active ingredients of the pharmaceutical compositions of this invention and are used in the methods of inhibiting H-2 histamine receptors according to this invention may be represented by the following formula, in which it will be understood that the structure of the nucleus is such that the bond between the carbon and nitrogen atoms might equally well be represented as a double bond:

FORSL'LA l in which:

A is a chain of 3 to 4 atoms of which 1 to 2 atoms are nitrogen or 1 of which is sulphur in the position alpha to the carbon atom and the remainder are carbon, which chain forms an unsaturated ring with the carbon and nitrogen atoms to which it is attached;

n is from 3 to 6;

R is hydrogen, lower alkyl, benzoyl or substituted or unsubstituted phenylethyl.

X is hydrogen, lower alkyl, halogen or lower alkylthio or a pharmaceutically acceptable acid addition salt thereof.

Preferably, the thiourea derivatives of the pharmaceutical compositions and methods of this invention are represented by Formula I in which:

A is such that with the carbon and nitrogen atoms shown it forms a thiazolyl ring or an imidazolyl ring, advantageously 4(5)-imidazolyl;

n is 4; Q

R is methyl and X is hydrogen or halogen, advantageously hydrogen or bromo or a pharmaceutically acceptable acid addition salt thereof.

Specific compounds which are found to be particularly useful are N -Methyl-N 4-( 4( 5 imidazolyl )butyl )thiourea, N-methyl-N 4-( 5-bromo- 4-imidazoly1)butyl)-thiourea and N-methyl-N-(4-(2- thiazolyl)buty1)thiourea. These compounds are referred to hereinafter as the specific preferred compounds.

The compounds of Formula I may be produced by processes which commence with an amino compound of the following formula:

rosurtu 11 in which A, X and n have the same significance as in Formula I.

The compounds of Formula I in which R is benzoyl may be prepared from an amine of Formula II by reaction with benzoyl isothiocyanate in an appropriate solvent such as chloroform. Alkaline hydrolysis of these compounds with a reagent such as aqueous potassium hydroxide or aqueous potassium carbonate yields the compounds of Formula I wherein R is hydrogen.

Compounds of Formula I wherein R is hydrogen may alternatively be prepared from the amine of Formula II by reaction at elevated temperature with the thiocyanate of ammonium or of a metal such as sodium or potassium. The compounds of Formula 1 where R is lower alkyl or substituted or unsubstituted phenylethyl may be prepared from the amine of Formula II by reaction with an isothiocyanic ester of formula R--N=C=S in an appropriate solvent such as chloroform, ethanol or acetonitrile. Alternatively the amine of Formula II may be converted by reaction with carbon disulphide to the dithiocarbamic acid of the formula:

FORMULA II I in which A, X and n have the same significance as in Formula I and R is hydrogen and then methylated to yield the compound of Formula ill in which R is methyl. Finally, reaction of this methyl ester with an amine of formula RNl-I wherein R is lower alkyl or substituted or unsubstituted phenylethyl yields the required compound of Formula I wherein R is lower alkyl or substituted or unsubstituted phenylethyl.

The dithiocarbamic acid of Formula III where R is hydrogen may alternatively be treated with a heavy metal saltsuch as mercuric acetate to form an isothiocyanate of the formula FORFTILA I? X c-(crmn-s-c-s A S V which may finally be treated with an amine of the formula RNH wherein R is hydrogen, lower alkyl or substituted or unsubstituted phenylethyl to yield the required compound of Formula I.

In the case of those compounds where X is not hydrogen, this substitutent may be introduced into the corresponding amine i.e. to form a compound of Formula II. For example the Z-methylthio-imidazolyl derivatives may be formed by methylation of the corresponding imidazole-Z-thiones and the 5(4)-bromo-imidazoles by the bromination of the corresponding compounds wherein X is hydrogen.

The pharmaceutical compositions of this invention to inhibit H-Z histamine receptors comprise a pharmaceutical carrier and a thiourea compound of formula I or a pharmaceutically acceptable acid addition salt thereof. The active ingredient will be present in the compositions of this invention in an effective amount to inhibit H-2 histamine receptors.

The method of inhibiting H-2 histamine receptors, according to this invention, comprises administering to an animal in an amount sufficient to inhibit H-2 histamine receptors a thiourea compound of formula I or a pharmaceutically acceptable acid addition salt thereof. The thiourea compound is preferably administered in a dosage unit form.

Another object of this invention is a method of inhibiting gastric acid secretion which comprises administering internally to an animal in an amount sufficient to inhibit gastric acid secretion a thiourea compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

The compounds 'of Formula I may be combined with a pharmaceutically acceptable carrier to form pharmaceutical compositions. Advantageously the compositions will be made up in a dosage unit form appropriate to the desired mode of administration. The pharmaceutical carrier employed may be, for example, either a solid or liquid.- Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Other pharmacologically active compounds may in certain cases be included in the pharmaceutical compositions.

As stated above the thiourea compounds of Formula I have been found to have pharmacological activity in the animal body as antagonists to certain actions of histamine which are not blocked by antihistamines such as mepyramine. For example, they have been found to inhibit selectively the histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane, at doses from 2 to 256 micromoles per kilogram intravenously. This procedure is described in the above-mentioned paper of Ash and Schild. The specific preferred compounds as hereinabove defined are active in this test at doses from 2 to 32 micromoles per kilogram and show a 50 percent inhibitory effect (lD at from 2 to 15 micromoles per kilogram. Similarly, the action of these compounds and compositions may, in many cases, be demonstrated by their antagonism to the effects of histamine on other tissues which, according to the above-mentioned paper of Ash and Schild, are not H-l receptors. Examples of such tissues are the lumen-perfused stomachs of anaesthetised cats, Heidenhain pouch dogs, perfused isolated guinea-pig heart, isolated guinea-pig right atrium and isolated rat uterus. For example, in isolated guinea-pig right atrium the specific preferred compounds show an ID of from 2 to 10 micromoles per litre.

The compounds of the method of this invention inhibit the secretion of gastric acid stimulated by pentagastrin or by food. In addition, these compounds also show anti-inflammatory activity in conventional tests suchas the rat paw oedema test and u.v. erythema test. In the rat paw oedema test where the oedema is induced by Bradykinin or by the histamine releasing agent known as compound 48/80, the paw volume is reduced significantly by subcutaneous injections of doses of aboutSOO micromoles/kg i.e. a dose per single rat of about 15mg. For example, in such a test, N- methyl-N'-(4(4(5 )-imidazolyl)butyl)thiourea reduced the volume of rat paw oedema induced by Bradykinin by percent. The level of activity found for the compounds used in the method of the present invention is illustrated by the effective dose range in the anaesthetized rat, that is from 8 to 256 micromoles per kilogram, g iven intravenously, and also by the dose effective in the rat paw oedema test.

A wide variety of pharmaceutical forms can be employed. Thus if a solid carrier is used, thepreparation can be tableted, placed in a hard gelatin" capsule in powder or pellet form, or in the form of 'atroche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gm. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceuticalcompositions are prepared by conventional techniques involving procedures such as mixing, granulatingand compressing ,or dissolving-the ingredients as appropriate to the'desired preparation.

The active ingredient will be present in'the composition'invan effective amount to inhibit H-2 histamine receptors. The route of administering may be internally e.g. orally, parenterally or may be topically.

l'n'the case of oral or parenteral administration, each dosage unit will preferably contain the-active ingredient in an amount of from about -100'mg'to about 250 mg. The active ingredient will preferably be administered in equal doses three to six .times:per'day.: The daily dosage regimen will preferably be from about 750 mg to about 1000 mg. l

' For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceutical composition comprising; as the or an'essential active ingredient at least one such compound in the basic form or in the form of an addition salt with a pharmaceutically acceptable acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric, picric and maleic acids .and.the addition salt with one of these acids may readily be converted to that with another. Such conversion may be effected by means of ionexchange techniques. A particularly useful method which also in many cases effects purification to a sufficient degree to allow the resultant solution of the addition salt to be used for pharmacological estimations involves the formation of the picrate salt and conversion therefrom to the chloride salt.

Advantageously the composition will be made up in a dosage form appropriate to the desired mode of administration for example, as a tablet, capsule, injectable solution or, when used as an anti-inflammatory agent, as aw cream for topical administration. v

The invention is illustrated but in no way limited by the following examples.

EXAMPLE 1 v Preparation of N-b enzoyl-N' 3- 4( 5 )-imida'z'olyl)propyl]thiourea A solution of benzoyl isothiocyanate 65.2 g) in chloroform is added. slowly. to a solution of 4(5 )-(3- aminopropyl)-imidazole (50.0 g) in chloroform 1.5 1.). The resultant solution is subsequently heated at reflux temperature for two hours and concentrated under reduced pressure. The residue isdissolved in ethanol and added to an excess of distilled water which results in the precipitation of a white solid. Recrystallization from ethyl acetate yields N-bepzoyl-N'-[3-(4(5)- imidazolyl)-propyl]thiourea, m.p. l45l48C.

EXAMPLE 2 Preparation, of N,- [3 -(4(5)-imidazoly1)propyllthiourea N-Benzoyl-N[3-(4(5-)-imidazoly1)propyl]thiourea (47 g) is added, with stirring, to a solution of potassium carbonate 13.8 g) in water (800 ml) at 6070 C ..S ubsequent heating at this temperature for 1 hour gives .a clear solution which is treated with charcoal andconcentrated to low bulk. Coling yields N-[3 (4(5.)

imidazolyl)propyl]thiourea, m.p. l49;l 5(:) "dC asa cob. orless solid. Analytically pure material having the same is obtained by, recrystallization from water. i

EXAMPLE 3 1 H -.-Preparation of v N-methyl-N'-[ 3-('fl(-5 )-imidazolyl)propyl]thiourea v Methyl isothiocyanate (2.92 g) is added to a solution of 4(5).(3-aminopropyl)irnidaiole (5.0 g) in chloroform ml) and dimethylformamide ("10 ml). The resultant solution isheated under reflux for 2.5 hours and evaporated to dryness The residue is treated with ethanolic hydrogen chloride which affords "a hygroscopic hydrochloride. This is recrystallized from ethanol-ether and converted to the base with aqueous potassium carbonate. Evaporation followed by extraction with ethanol yields the crude base which after recrystallisation from water yield' s pure N-methyl-N' (3-(4(5')-imidazolyl)propyl)thiourea," m.p. l-37C-. i I l I EXAMPLE 7 Preparationof N'-ethy1-N-( 3-(4( 5')-imidazolyl )propy1 )thiourea Ethyl isothiocyanate (4.2 is added slowly to a solution of 4(5)-(3-aminopropyl)imidazole (6.0 g) in acetonitrile (25 ml). The resultant solution is heated under reflux for 2 hours during which time a white solid is deposited. After cooling, the white solid is collected and washed with acetonitrile affording N-ethyl-N'-(3- (4(5 )-imidazolyl)propyl)thiourea, m.p. l45148C.

' I EXAMPLE5 Preparation of N-benzoyl-N '-(4-( 4.( 5 )-imidazolyl)butyl)thiourea Benzoyl isothiocyanate (7.5 g) is added dropwise to a solution of 4(5)-(4-aminobutyl)imidazole (4.8 g) in chloroform (350 ml) containing a little ethanol (1.6 g) and the mixture is boiled under reflux for 3 hours and then concentrated under reduced pressure. The residue 7 EXAMPLE 6 Preparation of N-[ 4-( 4( 5) -im'idazolyl )butyl thio urea N-Benzoyl-N-[4-(4(5 )-imidazo1yl)butyllthiourea hydrothiocyanate (1.5 g) is added with stirring to 10 percent aqueous potassium hydroxide (30 m1) at 657()?c, After15 minutes the mixture is cooled, acidi- I fied with dilute hydrochloric acid, and after 2 hours at 5" C is filtered from the benzoicacid which precipitates. The filtrate is basified with anhydrous potassium carbonate and concentrated to dryness under reduced pressure to yield a residue which isextracted with hot ethanol. Theextract-is concentratedto 5 mland cooled to yield colourless crystals. .-'l'l 1e latter,- after being crvstallized from water (9 ml) furnishes N-[4-(4(5)- imidazolyl)butyl ]thiourea, m.p. 166167C.

EXAMPLE7 I H Preparation of I N-methyl-N"-[4-(4( 5 )-imidazolyl )butyl ]thiourea {4(5) (4 Amihobutyl)imidaiole (15.9 g, containing EXAMPLE 8 Preparation of N-ethyl-N '-[4-(4( )-imidazolyl )butyl]thiourea 4(5)-(4-Aminobutyl)imidazole (2.0 g, containing 8 percent w/w ethanol) is caused to react with ethyl isothiocyanate 1.15 g) in acetonitrile by a procedure similar to that described in Example 7. Recrystallization from acetonitrile-isopropyl acetate finally affords N- ethyl-N 4-( 4( 5 )-imidazolyl )butyl )thiourea, m.p. 1 l41 16C.

EXAMPLE 9 Preparation of N-isopropyl-N'-( 4-(4( 5 )-imidazolyl )butyl )thiourea 4(5)-(4-aminobutyl)imidazole 1.3 g) is caused to react with isopropyl isothiocyanate (1.0 g) by a procedure similar to that described in Example 7. Recrystallization from aqueous isopropyl alcohol affords N- isopropyl-N'-(4-(4(5)-imidazolyl)butyl)thiourea m.p. 138-139C.

EXAMPLE 10 Preparation of N-( n-butyl )-N 4-( 4( 5 )-imidazolyl )butyl )thiourea 4(5)-(4-Aminobutyl)imidazole 2.0g, containing 8 percent w/w ethanol) is caused to react with n-butyl isothiocyanate (1.7 g) by a procedure similar to that described in Example 7. The product obtained is converted into its maleate salt with maleic acid in ethanol. Recrystallization from isopropyl alcohol-ether affords N-( n-butyl )-N'-(4-( 4( 5 )-imidazolyl )butyl thiourea maleate, m.p. l37l39C.

EXAMPLE 1 l Preparation of N-( Z-phenylethyl )-N '(4-( 5 imidazolyl )butyl )thiourea 4(5)-(4-Aminobutyl)imidazole (2.5 g, containing 8 percent w/w ethanol) is caused to react with 2- phenylethyl isothiocyanate (2.71 g) by a procedure similar to that described in Example 7. The product obtained is converted into its maleate salt with maleic acid in ethyl acetate. Recrystallization from isopropyl alcohol-ether affords N-(2-phenylethyl)-N'[4-( imidazolyl)-butyl]thiourea maleate, m.p. l24l26C.

EXAMPLE 12 Preparation of N-methyl-N 5-( 4( 5 )-imidazolyl )pentyl]thiourea i. A mixture of l-bromo-7-phthalimidoheptan-Z-one (obtainable from e-aminocaproic acid) (60.0 g) and formamide (360 ml) is heated at 180185C for 2 hours. Following removal of excess formamide by distillation under reduced pressure, the residue is hydrolysed by heating under reflux with 6N hydrochloric acid (1.8 l.) for 18 hours. After cooling to 0C and filtering to remove phthalic acid, the filtrate is concentrated under reduced pressure and the residue extracted with hot ethanol and again concentrated. The residual amine hydrochloride is converted to the free base by passage down an ion-exchange resin (OH) and elution with methanol. The base obtained is converted into the picrate with picric acid (82.5 g) in water. The picrate is recrystallized several times from water affording 4(5)-(5-amino-pentyl)imidazole dipicrate, m.p. 2092l 1C. Melting point of an analytically pure sample (from nitromethane) is 2 lO2l 1C.

The picrate is treated with hydrochloric acid in the usual way yielding the amine dihydrochloride which is finally converted to 4(5)-(5-aminopentyl)imidazole, m.p. 4548C., by passage down ion-exchange resin (OH).

ii. A solution of methyl isothiocyanate (2.92 g) and 4(5)-(5-aminopentyl)imidazole (6. l 3 g) in acetonitrile (40 ml) is heated under reflux for 3 hours. Cooling, followed by recrystallization of the product from acetonitrile affords N-methyl-N'[5-(4(5)-imidazolyl)pentyl]- thiourea, m.p. 108lO9C.

EXAMPLE 13 Preparation of N-( 2-p-hydroxpheny1 )ethyl )-N 4-(4( 5 )-imidazolyl butyl )thiourea Tyramine hydrochloride (4.4 g) is converted into its base with sodium (0.6 g) in ethanol. A solution prepared from the base in ethanol (200 ml) and water (6.5 ml) is added to a solution prepared from mercuric acetate (5.7 g) in ethanol (100 ml) containing water (3.3 ml). The resultant solution is diluted with a little water (3.5 ml) and added slowly to carbon disulphide (65 ml) under reflux. After addition, heating is continued for 3 hours, the mixture is filtered from mercuric sulphide and the filtrate is concentrated under reduced pressure. The residue is extracted with acetonitrile, filtered and the filtrate concentrated to afford p-hydroxyphenylethylisothiocyanate as a light yellow oil.

This is dissolved immediately in ethanol and 4-4(5)- aminobutylimidazole (2.2 g) is added. The solution is heated for 4 hours under reflux and concentrated under reduced pressure. The residue is chromatographed on a column of silica gel using ethyl acetate as eluant. The product obtained is recrystallized twice from isopropyl alcohol-ether to afford N-(Z-(phydroxyphenyl )ethyl )-N 4-( 4( 5 imidazolyl)butyl)thiourea (2.l g), m.p. ll72C.

EXAMPLE 14 Preparation of N-methyl-N 4-( 5 -bromo-4-imidazol;l )butyl )thiourea i. To a stirred mixture of (4(5 4- aminobutyl)imidazole (15.8 g, containing 8 percent weight/weight ethanol) in concentrated sulphuric acid (250 ml) is added silver sulphate (31.2 g). Light is excluded from the reaction mixture and bromine (10.75 m1) is added, followed by sulphuric acid washings (25 ml). The reaction mixture is stirred in the dark for 2-5 days, filtered and the precipitate washed with sulphuric acid (50 ml). The combined filtrates are added to water l L.) and neutralised topl-l 6-7 with sodium carbonate with cooling. Following filtration, the filtrate is concentrated under reduced pressure. The residue is converted to the hydrochloride using hydrogen chloride in isopropyl alcohol. The hydrochlorideis passed down Amberlite ion-exchange resin lRA 401 and eluted with water. The eluate is concentrated under reduced pressure and the residue extracted with methanol and diluted with ethanol yielding -bromo-4- aminobutylimidazole sulphate 15.8 g). Recrystallization from water-methanol-ethanol affords the analytically pure product (112 g), m.p. 92 95C.

ii. A solution of 5-bromo-4-aminobutylimidazole (2.39 g) prepared from the hydrochloride and potassium carbonate) and methyl isothiocyanate (0.73 g) in ethanol ml) is heated under reflux for 2 hours. Concentration followed by recrystallization of the residue twice from ethanol-ether affords N-methyl-N-(4- (5-bromo-4-imidazolyl)butyl)thiourea m.p. l53-155C.

EXAMPLE Preparation of N-methyl-N '-(4-( Z-methylthio- 4( 5 )imidazolyl )butyl )thiourea A solution of 4(5 )-(4-aminobutyl)imidazole-Z-thione (6 g) in methanol (200 ml) saturated with hydrogen chloride is boiled under reflux for 3 hours and then concentrated in vacuo. The resulting solid is recrystallized from ethanol to yield 2-methylthio-4(5)-(4- aminobutyl) imidazole dihydrochloride, (5.6 g) m.p. l8l182C. The latter (4.5 g) is neutralised with sodium hydroxide (1.4 g) in ethanol (100 ml) at 0C; the mixture is then filtered from sodium chloride, boiled under reflux for 2 hours with methyl isothiocyanate 1.46 g) and finally concentrated under reduced pressure. The resulting solid is extracted with isopropanol (3 X 100 ml) at 50C and the combined extracts are cooled to 0C. The material which crystallises out is collected and recrystallized from 85 percent ethanol to afford analytically pure (N-methyl N'-(4-(2- methylthio-4( 5 )imidazolyl )butyl )thiourea, m.p. l85l86C.

EXAMPLE 16 Preparation of N-methyl-N'-( 4-( 3-( 1.2,4-triazolyl )butyl)thiourea i. S-Phthalimidovaleroyl chloride (90.0 g) is added portionwise to a suspension of thiosemicarbazide (34.0 g) in anhydrous pyridine (220 ml) at 05C. After addition the mixture is kept at 0C for 1 hour and set aside overnight at room temperature. Following addition to water (2 l.) the white solid is collected and washed with 50 percent aqueous acetic acid and then water. Recrystallization from nitromethane affords l-( 5- (phthalimidovaleroyl) thiosemicarbazide (69 g), m.p.

- ii. 1-( 5-( Phthalimidovaleroyl )thiosemicarbazide (69 g) dissolved in a solution prepared from sodium (6.25 g) in ethanol (860 ml) is heated under reflux for 16 hours. Concentration to low bulk, followed by the addition of ice-water affords a white crystalline solid, which is collected and washedsuccessively with water, ethanol and ether to give 3-( 4-phthalimidobutyl)-l ,2,4- triazoline-S-thione (33 g). m.p. 2 23225C.

iii. The triazolinethione (30.5 g) is dissolved in ethanol (360 ml) and heated under reflux with stirring for 2 hours in the presence of Raney Nickel g). Filtration, followed'by concentration and the addition of water affords 3-(4-phthalimidobutyl)-l,2,4-triazole (13.3 g) m.p. 169l7lC. A sample recrystallised from water has m.p. l71l72C.

iv. The phthalimido derivative 13.0 g) is hydrolysed with 5N hydrochloric acid for 8 hours under reflux. Following cooling and removal of phthalic acid, the filtrate is concentrated. The solid residue is triturated with ethanol-ether (1:1) and filtered to afford 3-(4- aminobutyl-l,2,4-triazole dihydrochloride (10.0 g), m.p. 171-172c.

v. The am'ine' hydrochloride (5.0 g) is converted into its free base with aqueous potassium carbonate by concentration followed by extraction with ethanol-ether (3:1). The base is dissolved in ethanol and caused to react with methylisothiocyanate (1.87 g) in ethanol. The product obtained is recrystallized from water followed by ethanol-ether to afford N-methyl-N-(4-(3- 1,2,4-triazolyl)butyl )thiourea (3.15 g), m.p. l33l34C.

EXAMPLE 17 Preparation of N-methyl-N'-(4-( 2-pyridyl)butyl)thiourea i. 2-(3-cyanopropyl)pyridine (14.6 g) in dry ether ml) is added dropwise to a stirred suspension of lithium aluminum hydride (9.5 g) in dry ether"(300 EXAMPLE 18 Preparation of N-methyl-N 4-( Z-thiazolyl )butyl )thiourea i. Liquid ammonia (20 g) and 4- phthalimidovaleronitrile (67 g) is added to a cooled solution of hydrogen sulphide (50 g) in methyl alcohol (500 ml). The sealed reaction vessel is then heated at 40 for 3 days with stirring. Concentration followed by recrystallization from isopropyl acetate yields 4-phthalimidothiovaleramide, m.p. 143 1 46C ii. A mixture of the thioamide (11.0 g) and bromacetal (8.3 g) is heated for 1 hour on the steam-bath. Following filtration and washing with water, the crude product is dissolved in hydrochloric acid and precipitated by the addition of saturated sodium acetate. Recrystallization from isopropyl alcohol-water finally yeilds 2-(4-phthalimidobutyl)thiazole (5.22 g) m.p. 86-88C.

iii. 2-(4-Phthalimidobutyl)thiazole (5.0 g) is hydrolysed with hydrochloric acid in the usual way. The amine hydrochloride obtained is basified with potassium carbonate and extracted with ether-ethanol (3:1 to give 2-(4-amino-butyl)thiazole as a colourless oil. The reaction of the amine (2.0 g) and methyl isothiocyanate (0.98 g) in ethanol ml) for 1 hour, followed by chromatography of the product on silica gel with ethyl acetate as eluent gives N-methyl-N-(4-(2- thiazolyl)butyl) thiourea (2.5 g) as a colourless oil. Formation of the hydrobromide salt yields a crystalline solid, m.p. l30l32C. I

EXAMPLE 19 Ingredients Amounts N-methyl-N'-(4-(4(5)-imidazolyl)butyl)thiourea 150 mg Sucrose A 75 mg Starch 25 mg Talc 5 mg Stearic acid 2 mg The, ingredients are screened, mixed and filled into a hard gelatin capsule.

EXAMPLE 20 Ingredients Amounts N-methyl-N 4-( 5-bromo-4-imidazolyl )butyl 200 mg thiourea Lactose 100 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.

EXAMPLE 21 ingredients Amounts N-methyl-N'-(4-( Z-thiazolyl)butyl)thiourea 100 mg Lactose 75 mg Magnesium stearate 5 mg in which:

A is such that with the carbon and nitrogen atoms shown it forms-a thiazolyl, 1,2,4-triazolyl or pyridyl ring;

n is. from 3 to 6;

.R is hydrogen,.lo,wer alkyl, benzoyl, phenylethyl or 2-(hydroxyphenyl)ethyl; and

X is hydrogen, halogen or lower Valkylthio or a pharmaceutically acceptable acid addition salt thereof.

2. A pharmaceutical composition according to claim lain which the thiourea compound is N-methyl-N-(4- (2-thiazolyl)-butyl )thiourea.

3. A pharmaceutical composition according to claim 1 in which the thiourea compound isN-methyl-N-(4- (3-( l ,2,4-triazolyl))butyl)thiourea.

4. A pharmaceutical composition according to claim 1 in which the thiourea compound is N-methyl-N-(4- (2-pyridyl )-butyl )thiourea.

5. A method of inhibiting H-2 histamine receptors, said H-2 histamine receptors being those histamine receptors which are not inhibited by mepyramine but are inhibited by burimamide, .which comprises administering to an animal in need of inhibition of said H-2 histamine receptors in an amount sufficient to inhibit said H-2 histamine receptors a thiourea compound of the formula:

NHR

C NH :C

in which:

A is such that with the carbon and nitrogen atoms shown it forms a thiazolyl, 1,2,4-triaiolyl or pyridyl ring;

11 is from 3 to 6; I

R is hydrogen, lower alkyl, benzoyl, phenylethyl or 2-(hydroxyphenyl)ethyl; and

X is hydrogen, halogen or lower alkylthio or a pharmaceutically acceptable acid addition salt thereof.

6. A method according to claim 5 in which the thiourea compound is N-methyl-N'-(4-(3-( 1,2,4- triazo lyl )butyl )-thiourea.

7. A method according to claim 5 in which the thiourea compound is N-methyl-N-( 4-( 2- pyridyl )butyl )thiourea.

8.-A method according to claim 5 in which the thiourea compound is N-methyl-N'-(4-( 2- thiazolyl )butyl )thiourea.

9. A method of inhibiting gastric acid secretion which comprises administering internally to an animal in need of inhibition of gastric acid secretion in an amount sufficient to inhibit gastric acid secretion a thiourea compound of the formula:

NHIR

(' 2) NH c in which:

A is'such that with the carbon and nitrogen atoms shown it forms a thiazolyl, l,2,4-triazolyl or pyridyl ring;

n n is from 3 to 6;

R is hydrogen, lower alkyl, benzoyl, phenylethyl or 2-( hydroxyphenyl)ethyl; and

X is hydrogen, halogen or lower alkylthio or a pharmaceutically acceptable acid addition salt thereof. 

1. A PHARMACEUTICAL COMPOSITION TO INHIBIT H-2 HISTAMINE RECEPTORS, SAID H-2 HISTAMINE RECEPTORS BEING THOSE HISTAMINE RECPTORS WHICH ARE NOT INHIBITED BY MEPYRAMINE BUT ARE INHIBITED BY BURIMAMIDE, COMPRISING A PHARMACEUTICAL CARRIER AND, IN AN EFFECTIVE AMOUNT TO INHIBIT SAID H-2 HISTAMINE RECEPTORS, A THIOUREA COMPOUND OF THE FORMULA:
 2. A pharmaceutical composition according to claim 1 in which tHe thiourea compound is N-methyl-N''-(4-(2-thiazolyl)-butyl)thiourea.
 3. A pharmaceutical composition according to claim 1 in which the thiourea compound is N-methyl-N''-(4-(3-(1,2,4-triazolyl))butyl)thiourea.
 4. A pharmaceutical composition according to claim 1 in which the thiourea compound is N-methyl-N''-(4-(2-pyridyl)-butyl)thiourea.
 5. A method of inhibiting H-2 histamine receptors, said H-2 histamine receptors being those histamine receptors which are not inhibited by mepyramine but are inhibited by burimamide, which comprises administering to an animal in need of inhibition of said H-2 histamine receptors in an amount sufficient to inhibit said H-2 histamine receptors a thiourea compound of the formula:
 6. A method according to claim 5 in which the thiourea compound is N-methyl-N''-(4-(3-(1,2,4-triazolyl))butyl)-thiourea.
 7. A method according to claim 5 in which the thiourea compound is N-methyl-N''-(4-(2-pyridyl)butyl)thiourea.
 8. A method according to claim 5 in which the thiourea compound is N-methyl-N''-(4-(2-thiazolyl)butyl)thiourea.
 9. A method of inhibiting gastric acid secretion which comprises administering internally to an animal in need of inhibition of gastric acid secretion in an amount sufficient to inhibit gastric acid secretion a thiourea compound of the formula:
 10. A method of producing anti-inflammatory activity which comprises administering to an animal in need of said activity in an amount sufficient to produce said activity a thiourea compound of the formula: 